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Optimal elevation of ?-cell 11?-hydroxysteroid dehydrogenase type 1 is a compensatory mechanism that prevents high-fat diet-induced ?-cell failure.

ABSTRACT: Type 2 diabetes ultimately results from pancreatic ?-cell failure. Abnormally elevated intracellular regeneration of glucocorticoids by the enzyme 11?-hydroxysteroid dehydrogenase type 1 (11?-HSD1) in fat or liver may underlie pathophysiological aspects of the metabolic syndrome. Elevated 11?-HSD1 is also found in pancreatic islets of obese/diabetic rodents and is hypothesized to suppress insulin secretion and promote diabetes. To define the direct impact of elevated pancreatic ?-cell 11?-HSD1 on insulin secretion, we generated ?-cell-specific, 11?-HSD1-overexpressing (MIP-HSD1) mice on a strain background prone to ?-cell failure. Unexpectedly, MIP-HSD1(tg/+) mice exhibited a reversal of high fat-induced ?-cell failure through augmentation of the number and intrinsic function of small islets in association with induction of heat shock, protein kinase A, and extracellular signal-related kinase and p21 signaling pathways. 11?-HSD1(-/-) mice showed mild ?-cell impairment that was offset by improved glucose tolerance. The benefit of higher ?-cell 11?-HSD1 exhibited a threshold because homozygous MIP-HSD1(tg/tg) mice and diabetic Lep(db/db) mice with markedly elevated ?-cell 11?-HSD1 levels had impaired basal ?-cell function. Optimal elevation of ?-cell 11?-HSD1 represents a novel biological mechanism supporting compensatory insulin hypersecretion rather than exacerbating metabolic disease. These findings have immediate significance for current therapeutic strategies for type 2 diabetes.

SUBMITTER: Turban S

PROVIDER: S-EPMC3282808 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Optimal elevation of β-cell 11β-hydroxysteroid dehydrogenase type 1 is a compensatory mechanism that prevents high-fat diet-induced β-cell failure.

Turban Sophie S Liu Xiaoxia X Ramage Lynne L Webster Scott P SP Walker Brian R BR Dunbar Donald R DR Mullins John J JJ Seckl Jonathan R JR Morton Nicholas M NM

Diabetes 20120207 3

Type 2 diabetes ultimately results from pancreatic β-cell failure. Abnormally elevated intracellular regeneration of glucocorticoids by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in fat or liver may underlie pathophysiological aspects of the metabolic syndrome. Elevated 11β-HSD1 is also found in pancreatic islets of obese/diabetic rodents and is hypothesized to suppress insulin secretion and promote diabetes. To define the direct impact of elevated pancreatic β-cell 11β-HSD1 o ...[more]

PMID: 22315313

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Project description:Chronically elevated glucocorticoid levels impair cognition and are pro-inflammatory in the brain. Deficiency or inhibition of 11β-hydroxysteroid dehydrogenase type-1 (11β-HSD1), which converts inactive into active glucocorticoids, protects against glucocorticoid-associated chronic stress- or age-related cognitive impairment. Here, we hypothesised that 11β-HSD1 deficiency attenuates the brain cytokine response to inflammation. Because inflammation is associated with altered energy metabolism, we also examined the effects of 11β-HSD1 deficiency upon hippocampal energy metabolism. Inflammation was induced in 11β-HSD1 deficient (Hsd11b1Del/Del) and C57BL/6 control mice by intraperitoneal injection of lipopolysaccharide (LPS). LPS reduced circulating neutrophil and monocyte numbers and increased plasma corticosterone levels equally in C57BL/6 and Hsd11b1Del/Del mice, suggesting a similar peripheral inflammatory response. However, the induction of pro-inflammatory cytokine mRNAs in the hippocampus was attenuated in Hsd11b1Del/Del mice. Principal component analysis of mRNA expression revealed a distinct metabolic response to LPS in hippocampus of Hsd11b1Del/Del mice. Expression of Pfkfb3 and Ldha, key contributors to the Warburg effect, showed greater induction in Hsd11b1Del/Del mice. Consistent with increased glycolytic flux, levels of 3-phosphoglyceraldehyde and dihydroxyacetone phosphate were reduced in hippocampus of LPS injected Hsd11b1Del/Del mice. Expression of Sdha and Sdhb, encoding subunits of succinate dehydrogenase/complex II that determines mitochondrial reserve respiratory capacity, was induced specifically in hippocampus of LPS injected Hsd11b1Del/Del mice, together with increased levels of its product, fumarate. These data suggest 11β-HSD1 deficiency attenuates the hippocampal pro-inflammatory response to LPS, associated with increased capacity for aerobic glycolysis and mitochondrial ATP generation. This may provide better metabolic support and be neuroprotective during systemic inflammation or aging.

Dataset Information

Optimal elevation of ?-cell 11?-hydroxysteroid dehydrogenase type 1 is a compensatory mechanism that prevents high-fat diet-induced ?-cell failure.

Publications

Optimal elevation of β-cell 11β-hydroxysteroid dehydrogenase type 1 is a compensatory mechanism that prevents high-fat diet-induced β-cell failure.

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